Lysosomal TRP channels in metastatic melanoma Melanoma is the most aggressive form of skin cancer of the highest propensity to metastasize into the brain. Up to 75% of patients with advanced melanoma eventually develop brain metastases. Of patients with melanoma brain metastases (MBM), therapeutic regimens are quite limited and the 5-year survival rate is below 5%. Thus, it is of urgent need to develop new therapeutic strategies to specifically eradicate metastatic melanoma cells while sparing normal cells. We hypothesize that vesicular TRP channels can be pharmacologically targeted to reduce melanoma cell survival by modulating channel properties. We have developed a new method to measure lysosomal TRP channel activity of melanoma cells using genetically-engineered ion indicators and small-molecule TRPML1 modulator, ML-SAs. The primary goals of this R21 application are to test a clinically-relevant hypothesis that pharmacologically modulation of ML1 reduces melanoma cell survival. Aim 1 is to investigate the molecular mechanisms underlying ML-SA-induced melanoma cell susceptibility. Aim 2 is to determine the in vivo efficacy of ML-SAs in melanoma brain metastases mouse model. Our long-term goal is to develop new and efficient therapeutic approaches for eradicating metastatic melanoma.